JP2013506648A - Formulation of c-MET kinase inhibitor - Google Patents
Formulation of c-MET kinase inhibitor Download PDFInfo
- Publication number
- JP2013506648A JP2013506648A JP2012531499A JP2012531499A JP2013506648A JP 2013506648 A JP2013506648 A JP 2013506648A JP 2012531499 A JP2012531499 A JP 2012531499A JP 2012531499 A JP2012531499 A JP 2012531499A JP 2013506648 A JP2013506648 A JP 2013506648A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- sodium
- pharmaceutical composition
- met kinase
- kinase inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940125895 MET kinase inhibitor Drugs 0.000 title claims abstract description 23
- 239000000203 mixture Substances 0.000 title claims description 64
- 238000009472 formulation Methods 0.000 title claims description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 66
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 38
- 235000019359 magnesium stearate Nutrition 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 16
- 239000003085 diluting agent Substances 0.000 claims description 13
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 12
- 239000007884 disintegrant Substances 0.000 claims description 12
- 239000000314 lubricant Substances 0.000 claims description 12
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 11
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 10
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 10
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 10
- -1 1-methyl-1H-pyrazol-4-yl Chemical group 0.000 claims description 8
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000001727 in vivo Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 6
- 239000001095 magnesium carbonate Substances 0.000 claims description 6
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000002639 sodium chloride Nutrition 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 229920002472 Starch Polymers 0.000 claims description 5
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 235000014380 magnesium carbonate Nutrition 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- 229940032147 starch Drugs 0.000 claims description 5
- 239000000454 talc Substances 0.000 claims description 5
- 229910052623 talc Inorganic materials 0.000 claims description 5
- 229940033134 talc Drugs 0.000 claims description 5
- 235000012222 talc Nutrition 0.000 claims description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 4
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 claims description 4
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 235000021355 Stearic acid Nutrition 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- 239000011668 ascorbic acid Substances 0.000 claims description 4
- 229960005070 ascorbic acid Drugs 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000004220 glutamic acid Substances 0.000 claims description 4
- 235000013922 glutamic acid Nutrition 0.000 claims description 4
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 claims description 4
- 229940046813 glyceryl palmitostearate Drugs 0.000 claims description 4
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 239000011976 maleic acid Substances 0.000 claims description 4
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000019814 powdered cellulose Nutrition 0.000 claims description 4
- 229920003124 powdered cellulose Polymers 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- 235000010413 sodium alginate Nutrition 0.000 claims description 4
- 239000000661 sodium alginate Substances 0.000 claims description 4
- 229940005550 sodium alginate Drugs 0.000 claims description 4
- 239000008117 stearic acid Substances 0.000 claims description 4
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 235000010216 calcium carbonate Nutrition 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 229960002668 sodium chloride Drugs 0.000 claims description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 3
- 229960004274 stearic acid Drugs 0.000 claims description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
- KWMLJOLKUYYJFJ-GASJEMHNSA-N (2xi)-D-gluco-heptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C(O)=O KWMLJOLKUYYJFJ-GASJEMHNSA-N 0.000 claims description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 2
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 claims description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 2
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 claims description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 239000005995 Aluminium silicate Substances 0.000 claims description 2
- 241000416162 Astragalus gummifer Species 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims description 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 239000005913 Maltodextrin Substances 0.000 claims description 2
- 229920002774 Maltodextrin Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000005642 Oleic acid Substances 0.000 claims description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- 229920001100 Polydextrose Polymers 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229920001615 Tragacanth Polymers 0.000 claims description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- 229960000250 adipic acid Drugs 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 235000012211 aluminium silicate Nutrition 0.000 claims description 2
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 229960004365 benzoic acid Drugs 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 2
- 235000011010 calcium phosphates Nutrition 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 229940078456 calcium stearate Drugs 0.000 claims description 2
- KHAVLLBUVKBTBG-UHFFFAOYSA-N caproleic acid Natural products OC(=O)CCCCCCCC=C KHAVLLBUVKBTBG-UHFFFAOYSA-N 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 229920002301 cellulose acetate Polymers 0.000 claims description 2
- 229930016911 cinnamic acid Natural products 0.000 claims description 2
- 235000013985 cinnamic acid Nutrition 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 claims description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims description 2
- 229940043264 dodecyl sulfate Drugs 0.000 claims description 2
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002598 fumaric acid Drugs 0.000 claims description 2
- 229960005219 gentisic acid Drugs 0.000 claims description 2
- 239000000174 gluconic acid Substances 0.000 claims description 2
- 235000012208 gluconic acid Nutrition 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 229940097043 glucuronic acid Drugs 0.000 claims description 2
- 229940049654 glyceryl behenate Drugs 0.000 claims description 2
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 2
- 235000010417 guar gum Nutrition 0.000 claims description 2
- 239000000665 guar gum Substances 0.000 claims description 2
- 229960002154 guar gum Drugs 0.000 claims description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000000832 lactitol Substances 0.000 claims description 2
- 235000010448 lactitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims description 2
- 229960003451 lactitol Drugs 0.000 claims description 2
- 229940099563 lactobionic acid Drugs 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229940037627 magnesium lauryl sulfate Drugs 0.000 claims description 2
- 239000000395 magnesium oxide Substances 0.000 claims description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 2
- 235000012245 magnesium oxide Nutrition 0.000 claims description 2
- 229940057948 magnesium stearate Drugs 0.000 claims description 2
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 claims description 2
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229940035034 maltodextrin Drugs 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 2
- 229960002446 octanoic acid Drugs 0.000 claims description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 235000013856 polydextrose Nutrition 0.000 claims description 2
- 239000001259 polydextrose Substances 0.000 claims description 2
- 229940035035 polydextrose Drugs 0.000 claims description 2
- 229920000193 polymethacrylate Polymers 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 229940083037 simethicone Drugs 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 235000010487 tragacanth Nutrition 0.000 claims description 2
- 239000000196 tragacanth Substances 0.000 claims description 2
- 229940116362 tragacanth Drugs 0.000 claims description 2
- 229940074410 trehalose Drugs 0.000 claims description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 2
- 229960002703 undecylenic acid Drugs 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 claims 1
- 229960001230 asparagine Drugs 0.000 claims 1
- 229960003563 calcium carbonate Drugs 0.000 claims 1
- 239000000084 colloidal system Substances 0.000 claims 1
- 229960001708 magnesium carbonate Drugs 0.000 claims 1
- 229940099690 malic acid Drugs 0.000 claims 1
- 239000000377 silicon dioxide Substances 0.000 claims 1
- 235000012239 silicon dioxide Nutrition 0.000 claims 1
- 229940001593 sodium carbonate Drugs 0.000 claims 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims 1
- 239000008109 sodium starch glycolate Substances 0.000 claims 1
- 229920003109 sodium starch glycolate Polymers 0.000 claims 1
- 229940079832 sodium starch glycolate Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 229940126062 Compound A Drugs 0.000 description 29
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 29
- 239000002775 capsule Substances 0.000 description 19
- 229960004106 citric acid Drugs 0.000 description 19
- 230000002496 gastric effect Effects 0.000 description 17
- 229940079593 drug Drugs 0.000 description 14
- 239000008187 granular material Substances 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 9
- 229940043355 kinase inhibitor Drugs 0.000 description 8
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- 229960001021 lactose monohydrate Drugs 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 238000007908 dry granulation Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 239000004408 titanium dioxide Substances 0.000 description 3
- 235000010215 titanium dioxide Nutrition 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- WQNHWIYLCRZRLR-UHFFFAOYSA-N 2-(3-hydroxy-2,5-dioxooxolan-3-yl)acetic acid Chemical compound OC(=O)CC1(O)CC(=O)OC1=O WQNHWIYLCRZRLR-UHFFFAOYSA-N 0.000 description 2
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 2
- 208000006029 Cardiomegaly Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229940069428 antacid Drugs 0.000 description 2
- 239000003159 antacid agent Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 2
- 229960001596 famotidine Drugs 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000009474 hot melt extrusion Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- VMJFTOSOFDEKTM-UHFFFAOYSA-N 1-[2-(1-methylpyrazol-4-yl)-11-oxobenzo[1,2]cyclohepta[2,4-b]pyridin-9-yl]-n-(pyridin-2-ylmethyl)methanesulfonamide Chemical compound C1=NN(C)C=C1C1=CN=C(C=CC=2C(=CC(CS(=O)(=O)NCC=3N=CC=CC=3)=CC=2)C2=O)C2=C1 VMJFTOSOFDEKTM-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- 229920003083 Kollidon® VA64 Polymers 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- 108010079943 Pentagastrin Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 229940027088 carafate Drugs 0.000 description 1
- JTZPPHUZZDKEOC-RBQAPOGLSA-A chembl2367706 Chemical compound O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)OS(=O)(=O)O[C@@H]1[C@@H](OS(=O)(=O)O[Al](O)O)[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](COS(=O)(=O)O[Al](O)O)O[C@H]1O[C@@]1(COS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)O1 JTZPPHUZZDKEOC-RBQAPOGLSA-A 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229960004770 esomeprazole Drugs 0.000 description 1
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229960004872 nizatidine Drugs 0.000 description 1
- SGXXNSQHWDMGGP-IZZDOVSWSA-N nizatidine Chemical compound [O-][N+](=O)\C=C(/NC)NCCSCC1=CSC(CN(C)C)=N1 SGXXNSQHWDMGGP-IZZDOVSWSA-N 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 1
- 229960000444 pentagastrin Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012898 sample dilution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229940023144 sodium glycolate Drugs 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Images
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B66—HOISTING; LIFTING; HAULING
- B66C—CRANES; LOAD-ENGAGING ELEMENTS OR DEVICES FOR CRANES, CAPSTANS, WINCHES, OR TACKLES
- B66C23/00—Cranes comprising essentially a beam, boom, or triangular structure acting as a cantilever and mounted for translatory of swinging movements in vertical or horizontal planes or a combination of such movements, e.g. jib-cranes, derricks, tower cranes
- B66C23/18—Cranes comprising essentially a beam, boom, or triangular structure acting as a cantilever and mounted for translatory of swinging movements in vertical or horizontal planes or a combination of such movements, e.g. jib-cranes, derricks, tower cranes specially adapted for use in particular purposes
- B66C23/36—Cranes comprising essentially a beam, boom, or triangular structure acting as a cantilever and mounted for translatory of swinging movements in vertical or horizontal planes or a combination of such movements, e.g. jib-cranes, derricks, tower cranes specially adapted for use in particular purposes mounted on road or rail vehicles; Manually-movable jib-cranes for use in workshops; Floating cranes
- B66C23/44—Jib-cranes adapted for attachment to standard vehicles, e.g. agricultural tractors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B66—HOISTING; LIFTING; HAULING
- B66C—CRANES; LOAD-ENGAGING ELEMENTS OR DEVICES FOR CRANES, CAPSTANS, WINCHES, OR TACKLES
- B66C23/00—Cranes comprising essentially a beam, boom, or triangular structure acting as a cantilever and mounted for translatory of swinging movements in vertical or horizontal planes or a combination of such movements, e.g. jib-cranes, derricks, tower cranes
- B66C23/62—Constructional features or details
- B66C23/72—Counterweights or supports for balancing lifting couples
- B66C23/74—Counterweights or supports for balancing lifting couples separate from jib
- B66C23/76—Counterweights or supports for balancing lifting couples separate from jib and movable to take account of variations of load or of variations of length of jib
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Mechanical Engineering (AREA)
- Molecular Biology (AREA)
- Agronomy & Crop Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Jib Cranes (AREA)
Abstract
本発明は、ｃ−Ｍｅｔキナーゼ阻害剤を含有する医薬組成物に関する。また、前記医薬組成物を製造する方法も開示される。 The present invention relates to a pharmaceutical composition containing a c-Met kinase inhibitor. A method for producing the pharmaceutical composition is also disclosed.
Description
本発明は、ｃ−Ｍｅｔキナーゼ阻害剤の製剤に関する。 The present invention relates to formulations of c-Met kinase inhibitors.
細胞増殖性障害の治療をはじめとする、ｃ−Ｍｅｔキナーゼ機能と関連している種々の障害の治療のために、さまざまなｃ−Ｍｅｔキナーゼ阻害剤が開示されている。このような障害として、限定されないが、癌、肥厚化、再狭窄、心肥大免疫障害、及び炎症が挙げられる。ｃ−Ｍｅｔキナーゼ阻害剤の代表的な例として、全文が本明細書に援用される、Ｍｅｒｃｋ ＆ Ｃｏ．，Ｉｎｃ．の２００８年１月１７日に開示された国際公開ＷＯ２００８／００８３１０に開示されるものを包含する。 Various c-Met kinase inhibitors have been disclosed for the treatment of various disorders associated with c-Met kinase function, including the treatment of cell proliferative disorders. Such disorders include, but are not limited to, cancer, thickening, restenosis, cardiac hypertrophy immune disorders, and inflammation. As representative examples of c-Met kinase inhibitors, Merck & Co., which is incorporated herein in its entirety. , Inc. In the international publication WO2008 / 008310 disclosed on Jan. 17, 2008.
ｃ−Ｍｅｔキナーゼ阻害剤は、直接打錠、湿式造粒、ホットメルト押出、噴霧乾燥、及び／又はローラー圧縮法を使用することによって、錠剤として経口投薬用に製剤してもよい。同様に、ｃ−Ｍｅｔキナーゼ阻害剤は、ソフトカプセル剤中の液体であるゼラチンカプセル剤又は乾燥散剤又はハードカプセル剤中の半固体として経口投薬用に製剤してもよい。さらに、ｃ−Ｍｅｔキナーゼ阻害剤は、静脈内投薬用に製剤してもよい。 The c-Met kinase inhibitor may be formulated for oral administration as a tablet by using direct compression, wet granulation, hot melt extrusion, spray drying, and / or roller compression methods. Similarly, c-Met kinase inhibitors may be formulated for oral dosage as gelatin capsules that are liquid in soft capsules or semi-solids in dry powders or hard capsules. In addition, the c-Met kinase inhibitor may be formulated for intravenous dosing.
本発明の製剤は、ｃ−Ｍｅｔキナーゼ阻害剤のその他の製剤を上回る利点を有する。多数のｃ−Ｍｅｔキナーゼ阻害剤は、ｐＨ範囲１〜７の間中でｐＨ依存性溶解度を示し、酸性ｐＨでより高い溶解度を有する。ｐＨに対する溶解度の著しい依存に基づいて、これらの製剤の性能は、胃内ｐＨの可変性に基づいて変わり得ると仮定することができる。例えば、化合物Ａを用いる臨床研究から得られた最近のデータは、患者間での化合物Ａ曝露の高い可変性を示し、制酸薬を同時に服用していた（すなわち、高い胃内ｐＨを有する）一部の患者では低い曝露であった。曝露は、阻害剤が食品と一緒に摂取されるか否かをはじめ、多数の因子によって変わり得る。本発明の製剤は、その他の製剤よりも胃内ｐＨの変化に対する感受性が低い、薬物に対するインビボ曝露を与える。したがって、本発明の製剤は、その他の製剤と同様に高い、低い胃内ｐＨでの薬物に対する曝露を与え、本発明の製剤は、その他の製剤より高い、高い胃内ｐＨでの薬物に対する曝露を与える。 The formulations of the present invention have advantages over other formulations of c-Met kinase inhibitors. A number of c-Met kinase inhibitors show pH-dependent solubility between pH ranges 1-7, with higher solubility at acidic pH. Based on the significant dependence of solubility on pH, it can be assumed that the performance of these formulations can vary based on variability in gastric pH. For example, recent data obtained from clinical studies using Compound A showed a high variability in Compound A exposure between patients, taking antacids simultaneously (ie, having a high gastric pH). Some patients had low exposure. Exposure can vary depending on a number of factors, including whether the inhibitor is taken with the food. The formulations of the present invention provide in vivo exposure to drugs that are less sensitive to changes in gastric pH than other formulations. Thus, the formulations of the present invention provide exposure to drugs at low gastric pH, which is as high as other formulations, and the formulations of the present invention provide higher exposure to drugs at high gastric pH than other formulations. give.
本発明に記載される酸味料の使用は、酸味料の即時使用よりも有効である。例えば、酸味料のない単純製剤をベースラインとして、本発明の使用からの高ｐＨでの薬物可溶化の改善は、酸性飲料（例えば、コーラ）を同時投与することよりもかなり大きい。 The use of the acidulant described in the present invention is more effective than the immediate use of the acidulant. For example, based on simple formulations without acidulants, the improvement in drug solubilization at high pH from the use of the present invention is significantly greater than co-administering acidic beverages (eg, cola).
発明の要旨
本発明は、ｃ−Ｍｅｔキナーゼ阻害剤を含有する医薬組成物に関する。本発明の医薬組成物は、当技術分野で公知のその他の製剤よりも、胃内ｐＨの変化に対する感受性が低い薬物に対するインビボ曝露を与える。本発明の製剤は、当技術分野で公知のその他の製剤と比較して、同様に高い、低い胃内ｐＨでの薬物に対する曝露を与えるが、より高い、高い胃内ｐＨでの薬物に対する曝露を与える。
The present invention relates to a pharmaceutical composition containing a c-Met kinase inhibitor. The pharmaceutical compositions of the present invention provide in vivo exposure to drugs that are less sensitive to changes in gastric pH than other formulations known in the art. The formulations of the present invention provide exposure to drugs at a similarly high, low gastric pH, but higher exposure to drugs at high gastric pH compared to other formulations known in the art. give.
発明の詳細な記載
本発明は、ｃ−Ｍｅｔキナーゼ阻害剤を含有する医薬組成物に関する。本発明の医薬組成物は、当技術分野で公知のその他の製剤よりも、胃内ｐＨの変化に対する感受性が低い薬物に対するインビボ曝露を与える。本発明の製剤は、当技術分野で公知のその他の製剤と比較して、同様に高い、低い胃内ｐＨでの薬物に対する曝露を与えるが、より高い、高い胃内ｐＨでの薬物に対する曝露を与える。
Detailed Description of the Invention The present invention relates to pharmaceutical compositions containing c-Met kinase inhibitors. The pharmaceutical compositions of the present invention provide in vivo exposure to drugs that are less sensitive to changes in gastric pH than other formulations known in the art. The formulations of the present invention provide exposure to drugs at a similarly high, low gastric pH, but higher exposure to drugs at high gastric pH compared to other formulations known in the art. give.
特に有効なｃ−Ｍｅｔキナーゼ阻害剤として、１−［３−（１−メチル−１Ｈ−ピラゾール−４−イル）−５−オキソ−５Ｈ−ベンゾ［４，５］シクロヘプタ［１，２−ｂ］ピリシン−７−イル］−Ｎ−（ピリジン−２−イルメチル）メタンスルホンアミド As particularly effective c-Met kinase inhibitors, 1- [3- (1-methyl-1H-pyrazol-4-yl) -5-oxo-5H-benzo [4,5] cyclohepta [1,2-b] Pyridin-7-yl] -N- (pyridin-2-ylmethyl) methanesulfonamide
があり、これは、全文が本明細書に援用される、Ｍｅｒｃｋ ＆ Ｃｏ．，Ｉｎｃ．の２００８年１月１７日に公開された国際公開ＷＯ２００８／００８３１０に記載される手順によって調製できる。この化合物はまた、化合物Ａとしても知られている。 Which is Merck & Co., which is incorporated herein in its entirety. , Inc. Can be prepared by the procedure described in International Publication WO 2008/008310 published on Jan. 17, 2008. This compound is also known as Compound A.
本発明は、任意の薬学的に許容される増量剤／圧縮助剤、崩壊剤、超崩壊剤、滑沢剤、結合剤、界面活性剤、フィルムコーティング、及び溶媒の使用を考慮する。これらの成分の例は、以下に示されており、Ｈａｎｄｂｏｏｋ ｏｆ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｅｘｃｉｐｉｅｎｔｓ、第２版、Ａ．Ｗａｄｅ及びＰ．Ｊ．Ｗｅｌｌｅｒ編、１９９４年、Ｔｈｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｐｒｅｓｓ、Ｌｏｎｄｏｎ、Ｅｎｇｌａｎｄにより詳細に記載されている。 The present invention contemplates the use of any pharmaceutically acceptable filler / compression aid, disintegrant, superdisintegrant, lubricant, binder, surfactant, film coating, and solvent. Examples of these components are shown below and are described in Handbook of Pharmaceutical Excipients, 2nd edition, A.I. Wade and P.W. J. et al. Weller, 1994, The Pharmaceutical Press, London, England.
本発明は、５重量％〜８０重量％のｃ−Ｍｅｔキナーゼ阻害剤と、５重量％〜８０重量％の酸味料と、０重量％〜９０重量％の希釈剤と、０〜１５重量％の崩壊剤と、０〜５．０重量％の滑沢剤とを含む医薬組成物を含む。本発明の一クラスでは、３０重量％〜３５重量％のｃ−Ｍｅｔキナーゼ阻害剤と、４０重量％〜４５重量％の酸味料と、２０重量％〜２５重量％の希釈剤と、１．０重量％〜５．０重量％の崩壊剤と、０．５重量％〜２．０重量％の滑沢剤とを含む医薬組成物がある。 The present invention relates to 5-80% by weight c-Met kinase inhibitor, 5-80% by weight acidulant, 0-90% by weight diluent, 0-15% by weight. A pharmaceutical composition comprising a disintegrant and 0-5.0% by weight of a lubricant is included. In one class of the invention, 30% to 35% by weight c-Met kinase inhibitor, 40% to 45% acidulant, 20% to 25% diluent, 1.0% There is a pharmaceutical composition comprising from wt% to 5.0 wt% disintegrant and from 0.5 wt% to 2.0 wt% lubricant.
本発明の一実施態様では、酸味料に対するｃ−Ｍｅｔキナーゼ阻害剤の重量比は、０．３〜５．０の範囲内から選択される。 In one embodiment of the invention, the weight ratio of c-Met kinase inhibitor to sour agent is selected within the range of 0.3 to 5.0.
本発明の一実施態様では、ｃ−Ｍｅｔキナーゼ阻害剤は、１−［３−（１−メチル−１Ｈ−ピラゾール−４−イル）−５−オキソ−５Ｈ−ベンゾ［４，５］シクロヘプタ［１，２−ｂ］ピリジン−７−イル］−Ｎ−（ピリジン−２−イルメチル）メタンスルホンアミド（化合物Ａ）又はその薬学的に許容される塩である。 In one embodiment of the invention, the c-Met kinase inhibitor is 1- [3- (1-methyl-1H-pyrazol-4-yl) -5-oxo-5H-benzo [4,5] cyclohepta [1. , 2-b] pyridin-7-yl] -N- (pyridin-2-ylmethyl) methanesulfonamide (Compound A) or a pharmaceutically acceptable salt thereof.
本発明の一実施態様では、酸味料（ａｃｉｄｕｌｅｎｔ）は、酢酸、アジピン酸、ベンゼンスルホン酸、安息香酸、カプリル酸、桂皮酸、クエン酸、エタンジスルホン酸、酒石酸、アスコルビン酸、マレイン酸、グルタミン酸、乳酸、シュウ酸、Ｌ−アスパラギン酸、２−ヒドロキシエタンスルホン酸、パモ酸、マロン酸、ゲンチジン酸、サリチル酸、フマル酸、グルコヘプタン酸、グルコン酸、グルクロン酸、馬尿酸、ラクトビオン酸、ラウリル硫酸、リンゴ酸、マロン酸、マンデル酸、メタンスルホン酸、プロピオン酸、ステアリン酸、トルエンスルホン酸、ウンデシレン酸、カンファースルホン酸、及びオレイン酸からなる群から選択される。本発明の一クラスでは、酸味料（ａｃｉｄｕｌｅｎｔ）は、クエン酸である。 In one embodiment of the invention, the acidulant comprises acetic acid, adipic acid, benzenesulfonic acid, benzoic acid, caprylic acid, cinnamic acid, citric acid, ethanedisulfonic acid, tartaric acid, ascorbic acid, maleic acid, glutamic acid, Lactic acid, oxalic acid, L-aspartic acid, 2-hydroxyethanesulfonic acid, pamoic acid, malonic acid, gentisic acid, salicylic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glucuronic acid, hippuric acid, lactobionic acid, lauryl sulfate, It is selected from the group consisting of malic acid, malonic acid, mandelic acid, methanesulfonic acid, propionic acid, stearic acid, toluenesulfonic acid, undecylenic acid, camphorsulfonic acid, and oleic acid. In one class of the invention, the acidulant is citric acid.
本発明の一実施態様では、希釈剤は、微晶質セルロース、ラクトース、マンニトール、リン酸カルシウム、炭酸カルシウム、炭酸マグネシウム、スクロース、グルコース、ソルビトール、硫酸カルシウム、粉末セルロース、ケイ化微晶質セルロース、酢酸セルロース、圧縮糖、デキストレート、デキストリン、デキストロース、エチルセルロース（ｅｔｈｙｌｃｅｌｌｕｏｓｅ）、フルクトース、パルミトステアリン酸グリセリル、カオリン、ラクチトール、炭酸マグネシウム、酸化マグネシウム、マルトデキストリン、マルトース、中鎖トリグリセリド、ポリデキストロース、ポリメタクリレート、シメチコン、アルギン酸ナトリウム、塩化ナトリウム、トラガカント、トレハロース、キシリトール、及びデンプンからなる群から選択される。本発明の一クラスでは、希釈剤は、微晶質セルロースである。 In one embodiment of the present invention, the diluent is microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium carbonate, magnesium carbonate, sucrose, glucose, sorbitol, calcium sulfate, powdered cellulose, silicified microcrystalline cellulose, cellulose acetate. , Compressed sugar, dextrate, dextrin, dextrose, ethylcellulose, fructose, glyceryl palmitostearate, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylate, simethicone Selected from the group consisting of sodium alginate, sodium chloride, tragacanth, trehalose, xylitol, and starch . In one class of the invention, the diluent is microcrystalline cellulose.
本発明の一実施態様では、崩壊剤は、クロスカルメロースナトリウム、デンプン、クロスポビドン、グリコール酸ナトリウムデンプン、炭酸カルシウム、炭酸ナトリウム、炭酸マグネシウム、アルギン酸、三塩基性のリン酸カルシウム、カルシウムカルボキシメチルセルロース、ナトリウムカルボキシメチルセルロース、粉末セルロース、キトサン、コロイド状二酸化ケイ素、グアーガム、ヒドロキシプロピルセルロース、ケイ酸アルミニウムマグネシウム、メチルセルロース、ポビドン、及びアルギン酸ナトリウムからなる群から選択される。本発明の一クラスでは、崩壊剤は、クロスカルメロースナトリウムである。 In one embodiment of the invention, the disintegrant is croscarmellose sodium, starch, crospovidone, sodium glycolate starch, calcium carbonate, sodium carbonate, magnesium carbonate, alginic acid, tribasic calcium phosphate, calcium carboxymethyl cellulose, sodium carboxy Selected from the group consisting of methylcellulose, powdered cellulose, chitosan, colloidal silicon dioxide, guar gum, hydroxypropylcellulose, magnesium aluminum silicate, methylcellulose, povidone, and sodium alginate. In one class of the invention, the disintegrant is croscarmellose sodium.
本発明の一実施態様では、滑沢剤は、ステアリン酸マグネシウム、ステアリン酸、ナトリウムステアリルフマラート（ｓｏｄｉｕｍ ｓｔｅａｒｙｌ ｆｕｍｅｒａｔｅ）、タルク、ステアリン酸カルシウム、モノステアリン酸グリセリン、ベヘン酸グリセリル、パルミトステアリン酸グリセリル、ラウリル硫酸マグネシウム、中鎖トリグリセリド、ポロキサマー、安息香酸ナトリウム、塩化ナトリウム、ラウリル硫酸ナトリウム、及びステアリン酸亜鉛からなる群から選択される。本発明の一クラスでは、滑沢剤は、ステアリン酸マグネシウムである。 In one embodiment of the invention, the lubricant comprises magnesium stearate, stearic acid, sodium stearyl fumarate, talc, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, Selected from the group consisting of magnesium lauryl sulfate, medium chain triglycerides, poloxamer, sodium benzoate, sodium chloride, sodium lauryl sulfate, and zinc stearate. In one class of the invention, the lubricant is magnesium stearate.
本発明は、５重量％〜８０重量％のｃ−Ｍｅｔキナーゼ阻害剤と、５重量％〜８０重量％の酸味料と、０重量％〜９０重量％の希釈剤と、０〜１５重量％の崩壊剤と、０〜５．０重量％の滑沢剤とを含む医薬組成物を投与することによって、ｃ−Ｍｅｔキナーゼ阻害剤の吸収を改善する方法をさらに含む。本発明の一クラスでは、Ｃ−ｍｅｔキナーゼ阻害剤は、化合物Ａである。本発明の別のクラスでは、酸味料は、クエン酸であり、希釈剤は、微晶質セルロースであり、崩壊剤は、クロスカルメロースナトリウムであり、滑沢剤は、ステアリン酸マグネシウムである。 The present invention relates to 5-80% by weight c-Met kinase inhibitor, 5-80% by weight acidulant, 0-90% by weight diluent, 0-15% by weight. Further included is a method of improving absorption of a c-Met kinase inhibitor by administering a pharmaceutical composition comprising a disintegrant and 0-5.0 wt% lubricant. In one class of the invention, the C-met kinase inhibitor is Compound A. In another class of the invention, the sour agent is citric acid, the diluent is microcrystalline cellulose, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.
本発明は、酸味料に対するｃ−Ｍｅｔキナーゼ阻害剤の重量比が、０．３〜５．０の範囲内から選択される医薬組成物を投与することによって、ｃ−Ｍｅｔキナーゼ阻害剤の吸収を改善する方法をさらに含む。本発明の一クラスでは、Ｃ−ｍｅｔキナーゼ阻害剤は、化合物Ａであり、酸味料はクエン酸である。 The present invention provides absorption of a c-Met kinase inhibitor by administering a pharmaceutical composition wherein the weight ratio of the c-Met kinase inhibitor to the sour agent is selected from the range of 0.3 to 5.0. Further included is a method of improving. In one class of the invention, the C-met kinase inhibitor is Compound A and the acidulant is citric acid.
本発明は、製剤に酸味料（ａｃｉｄｕｌｅｎｔ）を組み込むことによって、ｃ−Ｍｅｔキナーゼ阻害剤を含有する製剤の溶解性能及びインビボ曝露を改善する方法をさらに含む。組成物への酸味料（ａｃｉｄｕｌｅｎｔ）の組み込みは、インビトロ又はインビボで予め溶解した同量の酸味料（ａｃｉｄｕｌｅｎｔ）を有することと比較して、高い胃内ｐＨに対応して、より高い溶解性能及びインビボ曝露をもたらす。 The invention further includes a method of improving the dissolution performance and in vivo exposure of a formulation containing a c-Met kinase inhibitor by incorporating an acidulant into the formulation. Incorporation of the acidulant into the composition results in higher dissolution performance, corresponding to a higher gastric pH, compared to having the same amount of acidulant pre-dissolved in vitro or in vivo. Provides in vivo exposure.
錠剤及びカプセル剤をはじめとする本発明の医薬組成物はまた、医薬製剤の技術分野で公知のさまざまな賦形剤から選択され得る１種以上のさらなる製剤成分を含有してもよい。組成物の所望の特性に従って、任意の数の成分を、医薬組成物の調製におけるその公知の用途に基づいて、単独で、又は組み合わせて選択してもよい。このような成分として、限定されないが、希釈剤、結合剤、圧縮助剤、崩壊剤、滑沢剤、流動促進剤、安定剤（乾燥性非晶質シリカなど）、フレーバー、フレーバー増強剤、甘味料、保存料、着色料、及びコーティングが挙げられる。 The pharmaceutical compositions of the present invention, including tablets and capsules, may also contain one or more additional formulation ingredients that may be selected from various excipients known in the pharmaceutical formulation art. Depending on the desired properties of the composition, any number of ingredients may be selected alone or in combination based on their known use in the preparation of pharmaceutical compositions. Such components include, but are not limited to, diluents, binders, compression aids, disintegrants, lubricants, glidants, stabilizers (such as dry amorphous silica), flavors, flavor enhancers, sweetness Include preservatives, preservatives, colorants, and coatings.
本明細書において用いる、用語「錠剤」とは、コーティングされているか否かに関らず、すべての形態及び大きさの圧縮された薬剤投与形製剤を包含するものとする。コーティングに使用してもよい物質として、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、二酸化チタン、タルク、甘味料、及び着色料が挙げられる。 As used herein, the term “tablet” is intended to encompass compressed drug dosage forms of all forms and sizes, whether coated or not. Materials that may be used for coating include hydroxypropyl methylcellulose, hydroxypropylcellulose, titanium dioxide, talc, sweeteners, and colorants.
本明細書において用いる、用語「カプセル剤」は、コーティングされているか否かに関らず、すべての形態及び大きさの圧縮された薬剤投与形製剤を包含するものとする。コーティングに使用してもよい物質として、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、二酸化チタン、タルク、甘味料、及び着色料が挙げられる。コーティングに使用してもよい物質として、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、二酸化チタン、タルク、甘味料、及び着色料が挙げられる。 As used herein, the term “capsule” is intended to encompass compressed drug dosage forms of all forms and sizes, whether coated or not. Materials that may be used for coating include hydroxypropyl methylcellulose, hydroxypropylcellulose, titanium dioxide, talc, sweeteners, and colorants. Materials that may be used for coating include hydroxypropyl methylcellulose, hydroxypropylcellulose, titanium dioxide, talc, sweeteners, and colorants.
本発明の医薬組成物は、細胞増殖性障害の治療をはじめとする、ｃ−Ｍｅｔキナーゼ機能と関連している障害の治療的又は予防的処置において有用である。このような障害として、限定されないが、癌、肥厚化、再狭窄、心肥大免疫障害、及び炎症が挙げられる。 The pharmaceutical compositions of the present invention are useful in the therapeutic or prophylactic treatment of disorders associated with c-Met kinase function, including the treatment of cell proliferative disorders. Such disorders include, but are not limited to, cancer, thickening, restenosis, cardiac hypertrophy immune disorders, and inflammation.
本発明の製剤は、ｃ−ｍｅｔキナーゼ阻害剤の生物学的利益が、正常よりも高い胃内ｐＨを有するもの（例えば、プロトンポンプ阻害剤などの胃内ｐＨ修飾薬を服用している患者）を含めた最大数の患者にわたって体験されることを確実にする。本発明の製剤は、限定されないが、オメプラゾール、ラベプラゾール（ｒａｂｅｒｐｒａｚｏｌｅ）、エソメプラゾール、ランソプラゾール、及びパントプラゾール（ｐａｔｏｐｒａｚｏｌｅ）をはじめとするプロトンポンプ阻害剤；限定されないが、シメチジン、ファモチジン、ニザチジン、及びラニチジンをはじめとするＨ−２遮断薬；及び限定されないが、カラフェート（ｃａｒａｆａｔｅ）、炭酸水素ナトリウム、炭酸カルシウム、水酸化マグネシウム、及び水酸化アルミニウムをはじめとする制酸薬の存在下で利益を提供するはずである。さらに、本発明の製剤は、胃内ｐＨの自然な被験体間変動に起因する（ｐＨ修飾薬に起因するのではなく）曝露の可変性を低減すると予想される。 The preparation of the present invention has a gastric pH in which the biological benefit of the c-met kinase inhibitor is higher than normal (for example, a patient taking a gastric pH modifier such as a proton pump inhibitor) To be experienced across the maximum number of patients, including Formulations of the present invention include, but are not limited to, proton pump inhibitors including but not limited to omeprazole, rabeprazole, esomeprazole, lansoprazole, and pantoprazole; cimetidine, famotidine, nizatidine, and ranitidine Provides benefits in the presence of antacids including, but not limited to, carafate, sodium bicarbonate, calcium carbonate, magnesium hydroxide, and aluminum hydroxide It should be. Furthermore, the formulations of the present invention are expected to reduce exposure variability due to natural subject-to-subject variation in gastric pH (rather than due to pH modifiers).
以下の実施例は、本発明を例示する目的で与えられるのであって、本発明の範囲に対する限定と解釈されるべきではない。 The following examples are given for the purpose of illustrating the invention and should not be construed as limitations on the scope of the invention.
乾燥造粒によるクエン酸を含む化合物Ａカプセル剤の調製 Preparation of compound A capsules containing citric acid by dry granulation
以下のように製造した顆粒剤をカプセルに封入することによって、カプセル剤（ＨＰＭＣシェル）を調製した。クエン酸、Ａｖｉｃｅｌ ＰＨ１０１、クロスカルメロースナトリウム、及び化合物Ａを、ドラムブレンダー中で一緒に混合する。混合物に、ステアリン酸マグネシウムの顆粒内部分（細かいスクリーンを使用して解凝集された）を加え、ブレンダーを使用して混合物を潤滑にした。潤滑にされたブレンドを、内蔵ミル及び粗目スクリーン（複数可）を備えたローラーコンパクターを使用して乾燥造粒した。ステアリン酸マグネシウムの顆粒外部分（細かいスクリーンを使用して解凝集された）を加え、ブレンダーを使用して混合することによって、得られた顆粒剤を潤滑にした。 Capsules (HPMC shell) were prepared by encapsulating granules produced as follows in capsules. Citric acid, Avicel PH101, croscarmellose sodium, and Compound A are mixed together in a drum blender. To the mixture was added the intragranular portion of magnesium stearate (deagglomerated using a fine screen) and the blend was lubricated using a blender. The lubricated blend was dry granulated using a roller compactor equipped with a built-in mill and coarse screen (s). The resulting granule was lubricated by adding the extragranular portion of magnesium stearate (deagglomerated using a fine screen) and mixing using a blender.
ホットメルト押出によるクエン酸を含む化合物Ａカプセル剤の調製 Preparation of compound A capsules containing citric acid by hot melt extrusion
化合物Ａ、クエン酸の共溶解物内部分、及びＫｏｌｌｉｄｏｎ ＶＡ６４を、Ｔｕｒｂｕｌａブレンダーを使用してガラス瓶中で一緒にブレンドした。ブレンドを手作業でゾーン７で１６ｍｍ ＴｈｅｒｍｏＥｌｅｃｔｒｏｎ押出機に入れた。ゾーン２〜８を連続的に冷却し、一方で、ゾーン９及び１０は、２００℃の設定点に加熱し、スクリュー速度は２００ＲＰＭとした。３ｍｍの円形オリフィスダイから出てくる押出物を回収し、空冷し、続いて、００３０スクリーンを備えたＦｉｔｚｍｉｌｌを６５００ＲＰＭで使用して練った。
Compound A, the inner part of the co-solution of citric acid, and Kollidon VA64 were blended together in a glass bottle using a Turbula blender. The blend was manually placed in a 16 mm ThermoElectron extruder in
次いで、共融解中間体のサンプルを、微晶質セルロース及びクエン酸の共融解物外部分と、ｔｕｒｂｕｌａブレンダーを使用してガラス瓶中でブレンドした。潤滑にされたブレンドを、スラッグ（すなわち、錠剤機上で作製された緩い圧縮粉）を粗目スクリーンに通すことによって乾燥造粒した。次いで、顆粒状物質をカプセルに詰めた。 The sample of eutectic intermediate was then blended with the microcrystalline cellulose and citric acid outer part in a glass bottle using a turbula blender. The lubricated blend was dry granulated by passing slug (ie, loose compressed powder made on a tablet machine) through a coarse screen. The granular material was then packed into capsules.
乾燥造粒によるクエン酸を含む化合物Ａ錠剤の調製 Preparation of Compound A tablets containing citric acid by dry granulation
以下のように調製した、顆粒を圧縮することによって、適したプレスを用いて錠剤を調製した。化合物Ａ及びＰＶＰを、Ａｖｉｃｅｌの顆粒内部分、クエン酸、及びクロスカルメロースナトリウムと一緒に、ブレンダー中で一緒に混合した。混合物に、ステアリン酸マグネシウムの顆粒内部分（細かいスクリーンを使用して解凝集された）を加え、ドラムブレンダーを使用して混合物を潤滑にした。潤滑にされたブレンドを、内蔵ミル及び粗目スクリーン（複数可）を備えたローラーコンパクターを使用して乾燥造粒した。ステアリン酸マグネシウムの顆粒外部分（細かいスクリーンを使用して解凝集された）を加え、ブレンダーを使用して混合することによって、得られた顆粒剤を潤滑にした。 Tablets were prepared using a suitable press by compressing the granules, prepared as follows. Compound A and PVP were mixed together in a blender with the intragranular portion of Avicel, citric acid, and croscarmellose sodium. To the mixture was added the intragranular portion of magnesium stearate (deagglomerated using a fine screen) and the mixture was lubricated using a drum blender. The lubricated blend was dry granulated using a roller compactor equipped with a built-in mill and coarse screen (s). The resulting granule was lubricated by adding the extragranular portion of magnesium stearate (deagglomerated using a fine screen) and mixing using a blender.
乾燥造粒した充填を用いるグルタミン酸を含む化合物Ａカプセル剤の調製 Preparation of compound A capsules containing glutamic acid using dry granulated filling
以下のように製造した顆粒剤をカプセルに封入することによって、カプセル剤（ハードゼラチンシェル）を調製した。グルタミン酸、Ａｖｉｃｅｌ ＰＨ１０１、ラクトース一水和物、クロスカルメロースナトリウム及び化合物Ａを、ドラムブレンダー中で一緒に混合する。混合物に、ステアリン酸マグネシウムの顆粒内部分（細かいスクリーンを使用して解凝集された）を加え、ブレンダーを使用して混合物を潤滑にした。潤滑にされたブレンドを、スラッグ（すなわち、錠剤機上で作製された緩い圧縮粉）を粗目スクリーンに通すことによって乾燥造粒した。ステアリン酸マグネシウムの顆粒外部分（スクリーンを使用して解凝集された）を加え、ブレンダーを使用して混合することによって、得られた顆粒剤を潤滑にした。 Capsules (hard gelatin shells) were prepared by encapsulating the granules produced as follows. Glutamic acid, Avicel PH101, lactose monohydrate, croscarmellose sodium and Compound A are mixed together in a drum blender. To the mixture was added the intragranular portion of magnesium stearate (deagglomerated using a fine screen) and the blend was lubricated using a blender. The lubricated blend was dry granulated by passing slug (ie, loose compressed powder made on a tablet machine) through a coarse screen. The resulting granules were lubricated by adding the extragranular portion of magnesium stearate (deagglomerated using a screen) and mixing using a blender.
乾燥造粒した充填を用いるアスコルビン酸を含む化合物Ａ錠剤の調製 Preparation of Compound A tablets containing ascorbic acid using dry granulated filling
錠剤機を使用して、以下のように製造した顆粒剤を圧縮することによって錠剤を調製した。アスコルビン酸、ＰＶＰ、Ａｖｉｃｅｌ ＰＨ１０１、ラクトース一水和物、クロスカルメロースナトリウム及び化合物Ａを、ドラムブレンダー中で一緒に混合する。混合物に、ステアリン酸マグネシウムの顆粒内部分（細かいスクリーンを使用して解凝集された）を加え、ブレンダーを使用して混合物を潤滑にした。潤滑にされたブレンドを、スラッグ（すなわち、錠剤機上で作製された緩い圧縮粉）を粗目スクリーンに通すことによって乾燥造粒した。ステアリン酸マグネシウムの顆粒外部分（スクリーンを使用して解凝集された）を加え、ブレンダーを使用して混合することによって、得られた顆粒剤を潤滑にした。 Tablets were prepared using a tablet machine by compressing the granules produced as follows. Ascorbic acid, PVP, Avicel PH101, lactose monohydrate, croscarmellose sodium and Compound A are mixed together in a drum blender. To the mixture was added the intragranular portion of magnesium stearate (deagglomerated using a fine screen) and the blend was lubricated using a blender. The lubricated blend was dry granulated by passing slug (ie, loose compressed powder made on a tablet machine) through a coarse screen. The resulting granules were lubricated by adding the extragranular portion of magnesium stearate (deagglomerated using a screen) and mixing using a blender.
乾燥造粒した充填を用いるマレイン酸を含む化合物Ａカプセル剤の調製 Preparation of Compound A capsules containing maleic acid using dry granulated filling
以下のように製造した顆粒剤をカプセルに封入することによって、カプセル剤（ハードゼラチンシェル）を調製した。マレイン酸、Ａｖｉｃｅｌ ＰＨ１０１、ラクトース一水和物、クロスカルメロースナトリウム及び化合物Ａを、ドラムブレンダー中で一緒に混合する。混合物に、ステアリン酸マグネシウムの顆粒内部分（細かいスクリーンを使用して解凝集された）を加え、ブレンダーを使用して混合物を潤滑にした。潤滑にされたブレンドを、スラッグ（すなわち、錠剤機上で作製された緩い圧縮粉）を粗目スクリーンに通すことによって乾燥造粒した。ステアリン酸マグネシウムの顆粒外部分（スクリーンを使用して解凝集された）を加え、ブレンダーを使用して混合することによって、得られた顆粒剤を潤滑にした。 Capsules (hard gelatin shells) were prepared by encapsulating the granules produced as follows. Maleic acid, Avicel PH101, lactose monohydrate, croscarmellose sodium and Compound A are mixed together in a drum blender. To the mixture was added the intragranular portion of magnesium stearate (deagglomerated using a fine screen) and the blend was lubricated using a blender. The lubricated blend was dry granulated by passing slug (ie, loose compressed powder made on a tablet machine) through a coarse screen. The resulting granules were lubricated by adding the extragranular portion of magnesium stearate (deagglomerated using a screen) and mixing using a blender.
乾燥造粒によるクエン酸を含む化合物Ａカプセル剤の調製 Preparation of compound A capsules containing citric acid by dry granulation
以下のように製造した顆粒剤をカプセルに封入することによって、カプセル剤（ハードゼラチンシェル）を調製した。クエン酸、ラウリル硫酸ナトリウム及び化合物Ａを、ドラムブレンダー中で一緒に混合する。混合物に、ステアリン酸マグネシウムの顆粒内部分（細かいスクリーンを使用して解凝集された）を加え、ブレンダーを使用して混合物を潤滑にした。潤滑にされたブレンドを、内蔵ミル及び粗目スクリーン（複数可）を備えたローラーコンパクターを使用して乾燥造粒した。ステアリン酸マグネシウムの顆粒外部分（細かいスクリーンを使用して解凝集された）を加え、ブレンダーを使用して混合することによって、得られた顆粒剤を潤滑にした。 Capsules (hard gelatin shells) were prepared by encapsulating the granules produced as follows. Citric acid, sodium lauryl sulfate and compound A are mixed together in a drum blender. To the mixture was added the intragranular portion of magnesium stearate (deagglomerated using a fine screen) and the blend was lubricated using a blender. The lubricated blend was dry granulated using a roller compactor equipped with a built-in mill and coarse screen (s). The resulting granule was lubricated by adding the extragranular portion of magnesium stearate (deagglomerated using a fine screen) and mixing using a blender.
絶食させた雄のビーグル犬における、化合物Ａ固体錠剤（１０ＭＧ用量／動物）の経口投与後の平均（ＳＥ）ＰＫパラメータ Mean (SE) PK parameters after oral administration of Compound A solid tablets (10 MG dose / animal) in fasted male Beagle dogs
高胃内ｐＨ（ファモチジン前処理した）ビーグル犬における動物研究を実施して、製剤を評価した。概して、クエン酸を含有する製剤（実施例１〜３）は、クエン酸を含有しない製剤と比較して、約２〜１０倍高い曝露を提供した。これらのデータは、クエン酸を含有する製剤は、当技術分野で公知のその他の製剤よりも、高胃内ｐＨ条件下で薬物に対する高い曝露を与えたという主張を支持する。正常な胃内ｐＨ（ペンタガストリン前処理した）ビーグル犬における動物研究は、クエン酸を含む製剤（実施例１）は、クエン酸を含まない対照製剤と比較して、同様に高い薬物に対する曝露を与えたことを示す。 Animal studies in high gastric pH (famotidine pretreated) beagle dogs were performed to evaluate the formulation. In general, formulations containing citric acid (Examples 1-3) provided about 2-10 times higher exposure compared to formulations without citric acid. These data support the assertion that formulations containing citric acid gave higher exposure to the drug under high gastric pH conditions than other formulations known in the art. Animal studies in normal intragastric pH (pentagastrin pretreated) beagle dogs showed that the formulation containing citric acid (Example 1) had a similar high drug exposure compared to the control formulation without citric acid. Indicates that it was given.
上記で言及された対照製剤は、化合物Ａ遊離塩基、ラクトース一水和物、及びステアリン酸マグネシウム（それぞれ、ｘ、ｙ、及びｚ ｍｇ／カプセル剤）の簡単なブレンドが詰められたハードゼラチンカプセル剤を含んでいたことは留意されたい。 The control formulation referred to above is a hard gelatin capsule filled with a simple blend of Compound A free base, lactose monohydrate, and magnesium stearate (x, y, and z mg / capsule, respectively) Note that it included.
化合物Ａ製剤のインビトロ溶解
ＵＳＰ装置ＩＩを使用するインビトロ溶解。
溶解媒体：ＳＧＦ ｐＨ３．０ １Ｌを作製するために、１Ｌの水に２ｇのＮａＣｌを溶解し、濃塩酸を使用してｐＨを３．０に調整する。
溶解容器温度：３７℃
櫂速度：１００ｒｐｍ
サンプル時点：５、１０、２０、３０分、及び必要に応じてとられるさらなる時点。
サンプリング容量：１．５ｍＬ
フィルター：Ｇｅｌｍａｎ ａｃｒｏｄｉｓｃ １μｍ ガラス繊維
希釈剤：５０／５０アセトニトリル／水＋０．０２％ ＴＦＡ（５００ｍＬのアセトニトリルを、５００ｍＬの水と混合し、２００μＬのＴＦＡを加える）
サンプル希釈：２５０μＬの濾過したサンプルを採取し、２５０μＬの希釈剤を用いて希釈する。
In vitro dissolution of Compound A formulations In vitro dissolution using USP apparatus II.
Dissolution medium: To make 1 L of SGF pH 3.0, 2 g NaCl is dissolved in 1 L water and the pH is adjusted to 3.0 using concentrated hydrochloric acid.
Melting vessel temperature: 37 ° C
Dredging speed: 100rpm
Sample time points: 5, 10, 20, 30 minutes, and additional time points taken as needed.
Sampling capacity: 1.5mL
Filter: Gelman acrodisc 1 μm glass fiber Diluent: 50/50 acetonitrile / water + 0.02% TFA (500 mL acetonitrile mixed with 500 mL water and 200 μL TFA added)
Sample dilution: Take 250 μL of filtered sample and dilute with 250 μL of diluent.
溶解サンプルの分析のためのＨＰＬＣ法：
カラム：Ｐｈｅｎｏｍｅｎｅｘ Ｌｕｎａ Ｃ１８、４．６ｍｍ×５０ｍｍ、３μｍ
移動相Ａ：水＋０．０２％ ＴＦＡ
移動相Ｂ：メタノール
溶出様式：イソクラティック（４５％ Ｂ）
カラム温度：４５℃
注入容量：２μＬ
検出器波長：２６０ｎｍ
流速：２ｍＬ／分
実施時間：２分
HPLC method for analysis of lysed samples:
Column: Phenomenex Luna C18, 4.6 mm × 50 mm, 3 μm
Mobile phase A: water + 0.02% TFA
Mobile phase B: Methanol Elution mode: Isocratic (45% B)
Column temperature: 45 ° C
Injection volume: 2 μL
Detector wavelength: 260 nm
Flow rate: 2 mL / min Implementation time: 2 minutes
図１から、本発明において記載される実施例１及び３〜７はすべて、関連時間スケール（１０〜３０分）下で、対照製剤よりも高度の溶解を与えることがわかる。 From FIG. 1 it can be seen that Examples 1 and 3-7 described in the present invention all give a higher degree of dissolution than the control formulation under the relevant time scale (10-30 minutes).
図１において言及される対照製剤は、化合物Ａ遊離塩基、ラクトース一水和物、及びステアリン酸マグネシウム（それぞれ、５０、９１、及び１．４２ｍｇ／カプセル剤）の簡単なブレンドで充填されたハードゼラチンカプセル剤を含むことは留意されたい。 The control formulation referred to in FIG. 1 is a hard gelatin filled with a simple blend of Compound A free base, lactose monohydrate, and magnesium stearate (50, 91, and 1.42 mg / capsule, respectively). Note that capsules are included.
化合物Ａの溶解度測定値
図２のグラフは、３００ｍｇのクエン酸が、２５０ｍＬのＳＧＦ ｐＨ３．０中に十分に溶解される場合の化合物Ａの達成される最大溶解度は、およそ１５ｍｇであることを示す。これは、１１０ｍｇ力価カプセル剤の１４％溶解に等しいと考えられる。しかし、４２重量％無水クエン酸を含有する化合物Ａ ＨＣｌ塩１１０ｍｇ ＨＰＭＣカプセル剤では、測定されたおよそ７８％溶解が達成されるので、製剤は溶解性能を改善している。この製剤内で、利用可能な無水クエン酸の量は、１６０．４４ｍｇである（カプセル剤の標的充填重量は、３８２．０ｍｇである）。
Compound A Solubility Measurements The graph of FIG. 2 shows that the maximum solubility achieved for Compound A is approximately 15 mg when 300 mg of citric acid is fully dissolved in 250 mL of SGF pH 3.0. . This is believed to be equivalent to 14% dissolution of a 110 mg titer capsule. However, with Compound A HCl salt 110 mg HPMC capsules containing 42% by weight citric anhydride, the formulation improves dissolution performance, as measured 78% dissolution is achieved. Within this formulation, the amount of citric anhydride available is 160.44 mg (the target fill weight of the capsule is 382.0 mg).
Claims (11)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24704609P | 2009-09-30 | 2009-09-30 | |
| US61/247,046 | 2009-09-30 | ||
| PCT/GB2010/051586 WO2011039527A1 (en) | 2009-09-30 | 2010-09-21 | Formulations for c-met kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2013506648A true JP2013506648A (en) | 2013-02-28 |
| JP5775085B2 JP5775085B2 (en) | 2015-09-09 |
Family
ID=42985941
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2012531499A Active JP5775085B2 (en) | 2009-09-30 | 2010-09-21 | Formulation of c-MET kinase inhibitor |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US9238571B2 (en) |
| EP (1) | EP2482803B1 (en) |
| JP (1) | JP5775085B2 (en) |
| AU (1) | AU2010302419B2 (en) |
| CA (1) | CA2772127A1 (en) |
| WO (1) | WO2011039527A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013506671A (en) * | 2009-09-30 | 2013-02-28 | メルク・シャープ・エンド・ドーム・コーポレイション | Crystalline hydrochloride of C-MET kinase inhibitor |
| JP2017002034A (en) * | 2015-06-04 | 2017-01-05 | ファイザー・インク | Solid dosage form of palbociclib |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9750700B2 (en) * | 2011-06-22 | 2017-09-05 | Natco Pharma Limited | Imatinib mesylate oral pharmaceutical composition and process for preparation thereof |
| US20160169413A1 (en) * | 2014-12-16 | 2016-06-16 | Caterpillar Inc. | Counterweight System and Method |
| AU2020242287A1 (en) | 2019-03-21 | 2021-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A Dbait molecule in combination with kinase inhibitor for the treatment of cancer |
| WO2021089791A1 (en) | 2019-11-08 | 2021-05-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for the treatment of cancers that have acquired resistance to kinase inhibitors |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
| US11891278B1 (en) * | 2022-08-31 | 2024-02-06 | Caterpillar Inc. | Lifting capacity systems and methods for lifting machines |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07324032A (en) * | 1994-05-30 | 1995-12-12 | Japan Energy Corp | Preparation of anti-aids agent and anti-aids preparation |
| WO2002020058A1 (en) * | 2000-09-06 | 2002-03-14 | Tanabe Seiyaku Co., Ltd. | Preparations for oral administration |
| JP2006526738A (en) * | 2003-06-03 | 2006-11-24 | シーメンス ヴィディーオー オートモティヴ コーポレイション | Method for reducing hydrocarbon emissions in fuel injection systems |
| WO2009008487A1 (en) * | 2007-07-12 | 2009-01-15 | Takeda Pharmaceutical Company Limited | Coated preparation |
| JP2009504796A (en) * | 2005-08-22 | 2009-02-05 | ノバルティス アクチエンゲゼルシャフト | PHARMACEUTICAL COMPOSITION COMPRISING A PH-DEPENDENT PHARMACEUTICAL COMPOUND, A PH ADJUSTING AGENT AND A RETARDANT |
| JP2009173622A (en) * | 2006-07-10 | 2009-08-06 | Merck & Co Inc | Tyrosine kinase inhibitor |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10209982A1 (en) | 2002-03-07 | 2003-09-25 | Boehringer Ingelheim Pharma | Dosage form to be administered orally for poorly soluble basic active ingredients |
| WO2003084931A1 (en) | 2002-04-02 | 2003-10-16 | Merck & Co., Inc. | 5h-benzo[4,5]cyclohepta[1,2-b]pyridine nmda/nr2b antagonists |
| JP4119478B1 (en) | 2005-06-23 | 2008-07-16 | メルク エンド カムパニー インコーポレーテッド | Tyrosine kinase inhibitor |
| TW200738638A (en) | 2005-06-23 | 2007-10-16 | Merck & Co Inc | Tyrosine kinase inhibitors |
| JP2009512706A (en) | 2005-10-21 | 2009-03-26 | メルク エンド カムパニー インコーポレーテッド | Tyrosine kinase inhibitor |
-
2010
- 2010-09-21 CA CA2772127A patent/CA2772127A1/en not_active Abandoned
- 2010-09-21 AU AU2010302419A patent/AU2010302419B2/en active Active
- 2010-09-21 US US13/498,600 patent/US9238571B2/en not_active Expired - Fee Related
- 2010-09-21 JP JP2012531499A patent/JP5775085B2/en active Active
- 2010-09-21 EP EP10759704.9A patent/EP2482803B1/en active Active
- 2010-09-21 WO PCT/GB2010/051586 patent/WO2011039527A1/en active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07324032A (en) * | 1994-05-30 | 1995-12-12 | Japan Energy Corp | Preparation of anti-aids agent and anti-aids preparation |
| WO2002020058A1 (en) * | 2000-09-06 | 2002-03-14 | Tanabe Seiyaku Co., Ltd. | Preparations for oral administration |
| JP2006526738A (en) * | 2003-06-03 | 2006-11-24 | シーメンス ヴィディーオー オートモティヴ コーポレイション | Method for reducing hydrocarbon emissions in fuel injection systems |
| JP2009504796A (en) * | 2005-08-22 | 2009-02-05 | ノバルティス アクチエンゲゼルシャフト | PHARMACEUTICAL COMPOSITION COMPRISING A PH-DEPENDENT PHARMACEUTICAL COMPOUND, A PH ADJUSTING AGENT AND A RETARDANT |
| JP2009173622A (en) * | 2006-07-10 | 2009-08-06 | Merck & Co Inc | Tyrosine kinase inhibitor |
| WO2009008487A1 (en) * | 2007-07-12 | 2009-01-15 | Takeda Pharmaceutical Company Limited | Coated preparation |
Non-Patent Citations (1)
| Title |
|---|
| JPN6014039481; ＳＴＲＥＵＢＥＬ， Ａ． ｅｔ ａｌ: 'ｐＨ-ｉｎｄｅｐｅｎｄｅｎｔ ｒｅｌｅａｓｅ ｏｆ ａ ｗｅａｋｌｙ ｂａｓｉｃ ｄｒｕｇ ｆｒｏｍ ｗａｔｅｒ-ｉｎｓｏｌｕｂｌｅ ａｎｄ -ｓｏｌｕｂｌｅ ｍａｔｒｉｘ ｔａｂｌｅｔｓ' Ｊ． Ｃｏｎｔｒｏｌ． Ｒｅｌｅａｓｅ Ｖｏｌ．６７， Ｎｏ．１, 2000, ｐ．１０１-１１０ * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013506671A (en) * | 2009-09-30 | 2013-02-28 | メルク・シャープ・エンド・ドーム・コーポレイション | Crystalline hydrochloride of C-MET kinase inhibitor |
| JP2017002034A (en) * | 2015-06-04 | 2017-01-05 | ファイザー・インク | Solid dosage form of palbociclib |
| JP2021167343A (en) * | 2015-06-04 | 2021-10-21 | ファイザー・インク | Solid dosage form of palbociclib |
Also Published As
| Publication number | Publication date |
|---|---|
| US20120241402A1 (en) | 2012-09-27 |
| EP2482803A1 (en) | 2012-08-08 |
| JP5775085B2 (en) | 2015-09-09 |
| CA2772127A1 (en) | 2011-04-07 |
| WO2011039527A1 (en) | 2011-04-07 |
| AU2010302419A1 (en) | 2012-02-16 |
| EP2482803B1 (en) | 2021-12-22 |
| US9238571B2 (en) | 2016-01-19 |
| AU2010302419B2 (en) | 2014-07-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5775085B2 (en) | Formulation of c-MET kinase inhibitor | |
| KR102336378B1 (en) | Pharmaceutical compositions comprising azd9291 | |
| KR102241643B1 (en) | Suspension for oral administration comprising amorphous tolvaptan | |
| US20030130268A1 (en) | Compositions controlling pH range of release and /or release rate | |
| KR101840182B1 (en) | Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactate monohydrate | |
| EP2623100A1 (en) | Preparation for improving solubility of poorly soluble drug | |
| EP1450770B1 (en) | Pharmaceutical composition comprising a 5ht1 receptor agonist | |
| JP7359764B2 (en) | Granules containing diamine derivatives | |
| CA2588465C (en) | Pharmaceutical composition containing an anti-nucleating agent | |
| JP4547888B2 (en) | Gastric buoyant solid preparation | |
| WO2010087358A1 (en) | Novel composition | |
| WO2019131891A1 (en) | Bitterness-masked drug-containing particles and formulation containing said drug-containing particles | |
| JP6123795B2 (en) | Controlled release pharmaceutical composition | |
| KR102286499B1 (en) | Pharmaceutical composition comprising lenalidomide | |
| US20150250720A1 (en) | Tablet containing composite with cyclodextrin | |
| KR102363727B1 (en) | Composition for preparing solid formulation containing pranlukast having enhanced bioavailability and production method thereof | |
| KR102308227B1 (en) | Oral tablet composition containing sunitinib | |
| WO2019016673A2 (en) | A stable oral pharmaceutical composition of imatinib | |
| US20210346303A1 (en) | Coating method | |
| AU2022383315A1 (en) | Solid dispersion, preparation method therefor, and solid formulation containing same | |
| CA3223889A1 (en) | Pharmaceutical compositions of an epidermal growth factor receptor inhibitor | |
| CN117355296A (en) | Prolonged release pharmaceutical composition for oral administration Shu Sai mex | |
| WO2010123443A1 (en) | Pharmaceutical composition comprising 4-amino-8-(2-fluoro-6-methoxy-phenyl)-n- propylcinnoline-3-carboxamide hydrogen sulphate. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20130913 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140924 |
|
| RD13 | Notification of appointment of power of sub attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7433 Effective date: 20141015 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20141015 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20141218 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150324 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20150609 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20150702 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5775085 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |